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    Summary
    EudraCT Number:2011-006087-49
    Sponsor's Protocol Code Number:MEK115306
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-04-24
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2011-006087-49
    A.3Full title of the trial
    A Phase III, randomized, double-blinded study comparing the combination of the BRAF inhibitor, dabrafenib and the MEK inhibitor, trametinib to dabrafenib and placebo as first-line therapy in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma
    Studio di fase III randomizzato, in doppio cieco, di confronto tra l'associazione inibitore di BRAF dabrafenib e inibitore di MEK trametinib e l'associazione dabrafenib e placebo nella terapia di prima linea di soggetti affetti da melanoma cutaneo non resecabile (stadio IIIc) o metastatico (stadio IV) positivo alla mutazione di BRAF V600E/K.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to test two investigational drugs, dabrafenib and trametinib, for treating melanoma
    Studio per sperimentare due farmaci, dabrafenib e trametinib, per il trattamento del melanoma
    A.4.1Sponsor's protocol code numberMEK115306
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGLAXOSMITHKLINE RESEARCH & DEVELOPMENT LTD.
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGLAXOSMITHKLINE
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline
    B.5.2Functional name of contact pointClinical Trials Helpdesk
    B.5.3 Address:
    B.5.3.1Street AddressIron Bridge Road
    B.5.3.2Town/ cityUxbridge
    B.5.3.3Post codeUB11 1BU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 20 89904466
    B.5.5Fax number+44 20 89901234
    B.5.6E-mailGSKClinicalSupportHD@gsk.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDABRAFENIB
    D.3.2Product code GSK2118436
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeGSK2118436
    D.3.9.3Other descriptive nameDABRAFENIB
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDABRAFENID
    D.3.2Product code GSK2118436
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeGSK2118436
    D.3.9.3Other descriptive nameDABRAFENIB
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTRAMETINIB
    D.3.2Product code GSK1120212
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeGSK1120212
    D.3.9.3Other descriptive nameTRAMETINIB
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTRAMETINIB
    D.3.2Product code GSK1120212
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeGSK1120212
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Cutaneous melanoma - aggressive form of skin cancers.
    Melanoma cutaneo - forma aggressiva di tumore della pelle
    E.1.1.1Medical condition in easily understood language
    Unresectable or metastatic BRAF-mutant melanoma
    Melanoma metastatico BRAF mutante non resecabile
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10025671
    E.1.2Term Malignant melanoma stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10025670
    E.1.2Term Malignant melanoma stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To establish the superiority of dabrafenib and trametinib combination therapy over dabrafenib and trametinib placebo (dabrafenib monotherapy) with respect to progression-free survival (PFS) for subjects with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.
    Dimostrare la superiorità della terapia di associazione dabrafenib-trametinib rispetto a dabrafenib e trametinib-placebo (monoterapia con dabrafenib) per quanto riguarda la sopravvivenza libera da progressione (PFS) in soggetti con melanoma cutaneo avanzato/metastatico positivo per la mutazione BRAF V600E/K.
    E.2.2Secondary objectives of the trial
    To compare dabrafenib and trametinib combination therapy with dabrafenib monotherapy for overall survival (OS), overall response rate (ORR), and duration of response • To characterize the safety of dabrafenib and trametinib combination therapy, including incidences of squamous cell carcinoma (SCC) and other proliferative cutaneous lesions; and • To characterize the concentrations of trametinib and of dabrafenib and its metabolites in subjects in the combination arm and of dabrafenib and its metabolites in the dabrafenib monotherapy arm.
    Confrontare la terapia di associazione dabrafenib-trametinib rispetto alla monoterapia con dabrafenib in termini di sopravvivenza globale (OS),tasso globale di risposta (ORR) e durata della risposta.Determinare la sicurezza dell’associazione dabrafenib-trametinib,compresa l’incidenza di carcinoma a cellule squamose (SCC) e di altre lesioni dermoproliferative; e Determinare le concentrazioni di trametinib e di dabrafenib e dei relativi metaboliti nel braccio di trattamento con l’associazione e le concentrazioni di dabrafenib e relativi metaboliti nel braccio di trattamento con dabrafenib in monoterapia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects eligible for enrolment in the study must meet all of the following criteria: 1. ≥ 18 years of age. 2. Signed written informed consent. 3. Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastic), and determined to be BRAF V600E/K mutationpositive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). The assay will be conducted by a central reference laboratory. Subjects with ocular or mucosal melanoma are not eligible. XML File Identifier: rSVgypuV11yA3U5AvZ/g44SU77Y= Page 23/37 4. Measurable disease (i.e., present with at least one measurable lesion per RECIST, version 1.1. Refer to Section 7.2.3.1 of protocol for the definition of a measureable lesion. 5. All prior anti-cancer treatment-related toxicities (except alopecia) must be ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 at the time of randomization. 6. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. 7. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception, as defined in Section 7.3.3 of protocol, throughout the treatment period, and for 30 days after the last dose of study treatment. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in Section 7.3.3 of protocol from 14 days prior to randomization, throughout the treatment period, and for 16 weeks after the last dose of study treatment. 8. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 9. Adequate baseline organ function as defined in Table 2 (page 25 of Protocol). 10. Subjects enrolled in France: In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
    1 Età 18 anni.2.Consenso informato scritto firmato. 3.Diagnosi istologica di melanoma cutaneo allo stadio IIIC (non resecabile) o allo stadio IV (metastatico) e con positività per le mutazioni BRAF V600E/K, determinata con il saggio bioMerieux (bMx) per uso esclusivamente sperimentale (investigational use only, IUO) THxID BRAF Assay (IDE: G120011). Il saggio diagnostico delle mutazioni tumorali sarà effettuato da un laboratorio di riferimento centralizzato. Non sono eleggibili i soggetti con melanoma oculare o mucoso. 4.Malattia misurabile (≥1 lesione misurabile secondo i criteri RECIST, versione 1.1 [Eisenhauer, 2009]).5. Alla randomizzazione, eventuali effetti tossici di pregresse terapie antineoplastiche (tranne l’alopecia) devono essere di Grado CTCAE ≤ 1 (Common Terminology Criteria for Adverse Events, versione 4.0; NCI, 2009).6.Il paziente deve essere in grado di assumere (ingoiare e trattenere) farmaci orali e non presentare alterazioni gastroenteriche significative che possano compromettere l’assorbimento (ad es. sindrome da malassorbimento o importanti resezioni gastriche o intestinali).7. Le donne in età fertile devono presentare un test di gravidanza negativo, eseguito nei 14 giorni precedenti la randomizzazione, e accettare di utilizzare un metodo contraccettivo efficace per tutta la durata della terapia dello studio e per i 30 giorni successivi all’assunzione dell’ultima dose. Anche gli uomini con partner femminili in età fertile, se non vasectomizzati, devono accettare di utilizzare un metodo contraccettivo efficace, iniziando 14 giorni prima della randomizzazione e continuando per tutta la durata della terapia dello studio e per 16 settimane dopo l’ultima dose.8.Performance status ECOG (Eastern Cooperative Oncology Group) pari a 0 o 1 [Oken, 1982]. Si veda all’Appendice 1 del protocollo per i dettagli.9.Funzionalità adeguata dei vari organi al basale.
    E.4Principal exclusion criteria
    1.Prior treatment with a BRAF inhibitor or a MEK inhibitor 2. Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed. (Ipilimumab treatment must end at least 8 weeks prior to randomization.)3. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomization. 4. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomization 5. prohibited medication 6. History of another malignancy. Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer, and/or subjects with indolent second malignancies are eligible 7.Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures.8. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed)9. A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.10. Brain metastasis are excluded unless: a. All known lesions were previously treated with surgery or stereotactic surgery (whole-brain radiation is not allowed unless given after definitive treatment with surgery or stereotactic surgery), AND b. Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for ≥ 12 weeks prior to randomization (stability must be confirmed with two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, AND c. Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to randomization, AND d. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to randomization In addition, for subjects that had brain metastases but currently have no evidence of disease (NED), NED for ≥12 weeks is required and must be confirmed by two consecutive scans, separated by ≥6 weeks, prior to randomization 11. A history or evidence of cardiovascular risk (see the protocol)12.A history or current evidence/risk of retinal vein occlusion (RVO) or CSR including: a. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or b. Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as: i. Evidence of new optic disc cupping;ii. Evidence of new visual field defects on automated perimetry; iii. Intraocular pressure >21 mmHg as measured by tonography. 13. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).14. Females who are nursing.
    1.Terapie pregresse con BRAF-inibitori o MEK-inibitori 2.Pregresse terapie antineoplastiche sistemiche (chemioterapia, immunoterapia, farmaci biologici, vaccini o farmaci sperimentali) per il melanoma di stadio IIIC (non resecabile) o di stadio IV (metastatico). Sono consentite pregresse terapie adiuvanti sistemiche. (la terapia con ipilimumab deve essere terminata almeno 8 settimane prima della randomizzazione).3Interventi chirurgici maggiori, radioterapia estesa, chemioterapia a tossicità ritardata, farmaci biologici o immunoterapia nei 21 giorni precedenti la randomizzazione, e/o chemioterapia quotidiana o settimanale senza potenziale tossicità ritardata, nei 14 giorni precedenti la randomizzazione. 4.Assunzione di un farmaco sperimentale nei 28 giorni precedenti la randomizzazione o entro un periodo di 5 emivite del farmaco (minimo 14 giorni) prima della randomizzazione, qualunque sia l’evenienza più breve. 5.Terapia in atto con farmaci non consentiti dal protocollo. 6.Anamnesi positiva per altre neoplasie. Eccezioni: sono eleggibili i soggetti senza malattia da 3 anni o con tumori cutanei diversi dal melanoma nei quali si è ottenuta la resezione completa e/o con neoplasie secondarie indolenti. 7.Patologie internistiche preesistenti gravi o instabili (diverse dalle neoplasie dell’eccezione al punto precedente), patologie psichiatriche o altre condizioni che possono compromettere la sicurezza del soggetto, la firma del consenso informato o l’aderenza alle procedure dello studio. 8.Infezione diagnosticata da virus dell’immunodeficienza umano (HIV), virus dell’epatite B (HBV) o dell’epatite C (HCV) (a eccezione delle infezioni croniche o risolte da HBV e HCV, che sono consentite). 9.Deficit di glucosio-6-fosfato deidrogenasi (G6PD).10. Le metastasi cerebrali sono motivo di esclusione tranne nei seguenti casi:a.Lesioni note asportate chirurgicamente o mediante chirurgia stereotassica (la radioterapia cerebrale totale non è consentita se non dopo ablazione chirurgica definitiva o ablazione mediante chirurgia stereotassica); b.Lesioni cerebrali, se ancora presenti, che si siano confermate stabili (non aumentate di dimensioni) per ≥12 settimane prima della randomizzazione (stabilità confermata da due risonanze magnetiche [RM] o tomografie computerizzate [TC] con mezzo di contrasto [mdc] consecutive); c.Lesioni asintomatiche che non richiedono la terapia corticosteroidea per ≥4 settimane prima della randomizzazione; d.Nessuna terapia anticonvulsivante che causi induzione enzimatica per ≥4 settimane prima della randomizzazione Inoltre, in caso di metastasi cerebrali senza segni di malattia (no evidence of disease, NED), la NED deve essere confermata per ≥12 settimane e documentata da due scansioni consecutive, intervallate di ≥6 settimane, prima della randomizzazione.11.Storia pregressa o evidenze di rischio cardiovascolare (si rimanda al protocollo)12.Storia pregressa o segni clinici/rischio di occlusione venosa retinica (retinal vein occlusion, RVO) o CSR, quali: a.Fattori predisponenti per RVO o CSR (ad es. ipertensione oculare o glaucoma non controllato, ipertensione non controllata, diabete mellito non controllato, sindromi da iperviscosità o ipercoagulabilità); o b.Patologie retiniche visibili diagnosticate mediante oftalmoscopia e considerate fattori di rischio per RVO o CSR, quali: i.Cupping del disco ottico (neuropatia ottica compressiva); ii.Difetti del campo visivo misurati con campimetria automatizzata; iii.Ipertensione oculare &gt;21 mmHg misurata mediante tonometria. 13.Ipersensibilità nota, immediata o ritardata, o allergia a farmaci chimicamente correlati ai farmaci dello studio, ai loro eccipienti e/o al dimetil-sulfossido (DMSO). 14.Allattamento al seno.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS; defined as the time from randomization until the earliest date of disease progression or death due to any cause).
    Sopravvivenza libera da progressione (PFS; definita come tempo intercorso tra la randomizzazione e la prima data di progressione di malattia o la morte per tutte le cause).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 8 and every 8 weeks thereafter through week 56 and then every 12 weeks thereafter (all +/- 7 days) until determination of progressive disease
    dalla settimana 8 e ogni 8 settimane successivamente fino alla settimana 56 e successivamente quindi ogni 12 settimane (tutti + /-7 giorni) fino a progressione della malattia
    E.5.2Secondary end point(s)
    Overall survival (OS; defined as the time from randomization until death due to any cause). Overall response rate (ORR; defined as the percentage of subjects with a confirmed or unconfirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1. Duration of response (defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among subjects who achieve an overall response [i.e., confirmed or unconfirmed CR or PR]). Safety as measured by clinical assessments including vital signs and physical examinations, 12-lead electrocardiograms (ECG), echocardiogram (ECHO), chemistry and hematology laboratory values, and adverse events (AEs). Concentrations of trametinib and of dabrafenib and its metabolites (GSK2285403, GSK2298683, and GSK2167542) in the combination arm and dabrafenib and its metabolites in the dabrafenib monotherapy arm
    Sopravvivenza globale (OS; definita come tempo intercorso dalla randomizzazione alla morte per tutte le cause). Tasso globale di risposta (ORR; definito come % soggetti con risposta completa [complete response, CR] confermata o non confermata, o risposta parziale [partial response, PR], valutata in qualsiasi momento secondo i criteri RECIST [Response Evaluation Criteria in Solid Tumors], versione 1.1 [Eisenhauer, 2009]). • Durata della risposta (definita come tempo intercorso tra la prima evidenza documentata di CR o PR fino alla progressione di malattia o alla morte per tutte le cause nei soggetti che hanno ottenuto una risposta globale [CR o PR confermata o non confermata]). • Sicurezza, in base alla valutazione clinica: segni vitali ed esame obiettivo, ECG a 12 derivazioni, ecocardiografia (ECO), parametri ematochimici ed ematologici ed eventi avversi (AE).• Concentrazioni di trametinib e di dabrafenib e relativi metaboliti (GSK2285403, GSK2298683 e GSK2167542) nel braccio di trattamento con l’associazione e di dabrafenib e dei relativi metaboliti nel braccio di trattamento con dabrafenib in monoterapia.
    E.5.2.1Timepoint(s) of evaluation of this end point
    OS will be assessed every 12 weeks after treatment discontinuation ORR and duration of response will be calculated based on the disease assessment schedule of Week 8 and every 8 weeks thereafter through week 56, and then every 12 weeks thereafter (all +/- 7 days) until determination of progressive disease All safety assessments will be performed at baseline and then every 4 weeks, except ECG and ECHOs, which will be done every 12 weeks. PK samples will be collected every 8 weeks through week 24. Three blood samples will be collected at Week 8: predose, 1-3 hours post dose, and 4-6 hours post dose. One blood sample will be obtained at Weeks 16 and 24.
    •Sopravvivenza globale• Tasso globale di risposta confermata o non confermata, o risposta parziale valutata in qualsiasi momento secondo i criteri RECIST •Durata della risposta (definita come tempo intercorso tra la prima evidenza documentata di CR o PR fino alla progressione di malattia o alla morte per tutte le cause nei soggetti che hanno ottenuto una risposta globale •Sicurezza, in base alla valutazione clinica: segni vitali ed esame obiettivo, ECG a 12 derivazioni, ecocardiografia (ECO), parametri ematochimici ed ematologici ed eventi avversi•Concentrazioni di trametinib e di dabrafenib e relativi metaboliti nel braccio di trattamento con l’associazione e di dabrafenib e dei relativi metaboliti nel braccio di trattamento con dabrafenib in monoterapia.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    Tollerabilità
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA80
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Canada
    Russian Federation
    Ukraine
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Subjects will receive study treatment until disease progression, death, unacceptable AE or subjects withdrawing consent will result in end of treatment. Thereafter subjects will be followed up until death
    I soggetti riceveranno il trattamento in studio fino a progressione della malattia, morte, eventi avversi inaccettabili o al ritiro del consenso. Successivamente verranno seguiti nel programma survival follow up fino a morte
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 265
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 75
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 220
    F.4.2.2In the whole clinical trial 340
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects in both arms will continue treatment until disease progression, death, unacceptable toxicity, or withdrawal of consent. Continuing treatment for a subject who has met protocol criteria for disease progression but is receiving clinical benefit (i.e., improvement compared to baseline status) can be considered in consultation with the GSK medical monitor.
    I soggetti in entrambi i bracci di trattamento continueranno la terapia fino al verificarsi di progressione di malattia, morte, tossicità inaccettabile o ritiro del consenso. Dopo aver consultato il Medical Monitor GSK, si potrà valutare la prosecuzione della terapia in soggetti che rientrano nei criteri stabiliti dal protocollo per la progressione di malattia (RECIST 1.1) ma che stanno traendo benefici clinici dalla terapia (miglioramento del quadro clinico rispetto al basale).
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-06-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-04-20
    P. End of Trial
    P.End of Trial StatusCompleted
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